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Targeting micrornas mir-409-5p, mir-379 and mir-154* to treat prostate cancer bone metastasis and drug resistant lung cancer

a technology of micrornas and prostate cancer, applied in the field of micrornas and cancer, can solve problems such as ineffective treatment, and achieve the effects of reducing or steady expression level, increasing expression level of meg9, and reducing the likelihood of drug responsiveness

Inactive Publication Date: 2014-10-30
CEDARS SINAI MEDICAL CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a method for predicting the response of cancer patients to drug treatment by testing biological samples for specific microRNAs (small RNA molecules) that are associated with an increased or decreased likelihood of drug responsiveness. By measuring the levels of these microRNAs, a patient's cancer can be classified as sensitive or resistant to treatment. This method can help improve the effectiveness of cancer treatment and prevent the development of drug resistance.

Problems solved by technology

Advanced-stage cancer patients develop bone metastases either with or without hormonal therapy, radiation therapy, chemotherapy, and immunotherapy, and currently there is no effective treatment.

Method used

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  • Targeting micrornas mir-409-5p, mir-379 and mir-154* to treat prostate cancer bone metastasis and drug resistant lung cancer
  • Targeting micrornas mir-409-5p, mir-379 and mir-154* to treat prostate cancer bone metastasis and drug resistant lung cancer
  • Targeting micrornas mir-409-5p, mir-379 and mir-154* to treat prostate cancer bone metastasis and drug resistant lung cancer

Examples

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example 1

MicroRNA Expression Profiling of Bone Metastatic Models of Prostate Cancer Reveal Elevated Expression of miR-409-5p

[0155]MiRNA profiling of two PCa bone metastatic cell based models derived from PCa patients, i.e. the human ARCaP model (ARCaPE and ARCaPM) (E-epithelial, M-mesenchymal), were performed (FIG. 1A) and the LNCaP model (LNCaP and C4-2) (15,16). The ARCaPE and LNCaP are less aggressive and do not metastasize to the bone, whereas the C4-2 and ARCaPM are highly aggressive and metastasize to the bone. Of these cell lines, miR-409-5p, miR-379 and miR-154* are upregulated in the highly bone metastatic ARCaPM cells (FIG. 1D). miR-409-5p is generated from immature transcript and transcribed form 5′ end of the pre-miRNA. The ARCaPM cells have 100% bone metastatic ability when injected intra-cardially into mice (17). The ARCaP model is an epithelial to mesenchymal transition model (17). Consistent with previously described EMT associated miRNAs, the miR-200 family members are highe...

example 2

Overexpression of miR-409 in Normal Prostate Gland Results in Tumor Growth

[0156]To test if miR-409 is oncogenic, the inventors injected human embryonic kidney, 293T cells transfected with miR-409 expressing lentiviral vector carrying green fluorescent protein (GFP) or control vector carrying GFP plasmid (System biosciences). The 293T cells were injected orthotopically into nude mice and tumor development was monitored using tumor specific infrared dye (IR783) (19). The rationale behind this procedure is that lentivirus will be secreted by the producer cells (293T) and infect prostate epithelia and stroma. Strikingly, tumors developed in three to five months in three out of four mice in miR-409 expressing prostates (FIG. 3A). The control mice did not develop tumors. The tumors had green fluorescence and showed tumor specific dye intake (FIG. 3A). Tumor sections were formalin fixed and paraffin embedded and H&E staining was performed. Tumor sections were graded by a pathologist. The t...

example 3

Inhibition of miR-409-5p in Mesenchymal Type Metastatic Prostate Cancer Cells (ARCaPM) Results in Cell Death, Upregulation of miR-409-5p Target Genes (Tumor Suppressors) and Reversion of Epithelial to Mesenchymal Transition (EMT to MET)

[0157]Inhibition of miR-409-5p using a lentiviral based anti-miR-409-5p resulted in significant cell death of metastatic prostate cancer cells (FIG. 4A). miR-409-5p expression was decreased in ARCaPM cells stably transfected with miR-409-5p inhibitor construct compared to control. miR-409-5p target mRNAs including TUSC4, PHC3 and STAG2 were evaluated and these were increased in miR-409-5p knockdown cells (ARCaPM-409-5pi) metastatic prostate cancer cells compared to the ARCaPM control (ARCaPM-C) cells. TUSC4 is a tumor suppressor protein deleted in solid tumors. PHC3 is part of the polycomb group proteins involved in transcriptional repression and regulation of cell fate (20). The siRNA-mediated down-regulation of TUSC4 induced cell proliferation, whil...

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Abstract

The present invention describes methods of treating cancer, cancer metastasis, and drug resistant cancers using miRNA inhibitors; for example, inhibitors of miR-409-5p. Also described are methods of using the miRNA as biomarkers; for example, to predict responsiveness to a cancer drug, to detect a disease state of cancer.

Description

STATEMENT REGARDING FEDERALLY-SPONSORED RESEARCH[0001]The U.S. Government has a paid-up license in this invention and the right in limited circumstances to require the patent owner to license others on reasonable terms as provided for by the terms of Grant No. CA122602 awarded by the National Institutes of Health.FIELD OF INVENTION[0002]This invention relates to micro RNAs and cancer; particularly, to prostate cancer bone metastasis and drug resistant lung cancer.BACKGROUND[0003]All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior ar...

Claims

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Application Information

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IPC IPC(8): C12N15/113C12Q1/68G01N33/50
CPCC12N15/113C12Q1/6886G01N33/5011C12Q2600/106C12Q2600/158C12Q2600/178A61K31/7105A61K31/713A61P11/00A61P13/08A61P15/00A61P19/00A61P35/00A61P35/04
Inventor CHUNG, LELAND W.K.JOSSON, SAJNIGURURAJAN, MURALIJAIN, ANJALI
Owner CEDARS SINAI MEDICAL CENT
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